In response to a strong, unanimous recommendation by the Data Safety and Monitoring Board (DSMB), this application seeks funding to extend randomized treatment and follow-up for the multivitamin (Centrum Silver) component of the Physicians Health Study II, an ongoing randomized, double-blind, placebo- controlled trial of vitamin E, vitamin C, and a multivitamin, in the prevention of cancer, cardiovascular disease, eye disease, and decline in cognitive function among 14,641 U.S. male physicians aged 50 years or older. The vitamin E and C arms of the trial will be terminated as scheduled in 2007. We propose to extend the multivitamin component of the trial for additional 4 years resulting in 12.2 years of total treatment and follow-up, in order to provide definitive answers to the questions of potential benefits in the prevention of chronic disease and possible risk of long-term use of multivitamins. Tens of billions of dollars are spent on multivitamins each year in the United States. About half of all adults in the United States take vitamin supplements. The widespread use of multivitamins makes the question of benefit as well as any risk timely and important. At a recent State-of-the-Science Conference sponsored by the NIH the summary statement indicated that the present evidence is insufficient to recommend either for or against the use of multivitamins to prevent chronic disease and that trials are essential in order to provide information for consumers. The PHS II is the only large-scale randomized trial testing a multivitamin in the prevention of chronic disease. No other trials are testing a multivitamin for the prevention of chronic disease and it is not likely that this trial will be repeated. After 6.9 mean years of follow-up, overall compliance with study pills is 76% and morbidity and mortality follow-up rates are excellent (98% and 100%, respectively). Since the costs of recruiting and randomizing 14,641 men into PHS II have already been covered, as well as the costs of conducting an average of 8.3 years of treatment and follow-up, the proposed continuation of the multivitamin arm of PHS II represents an extremely cost-effective trial considering its size and potential to answer critical questions. Direct costs for continuing the multivitamin arm of the trial are about $100 per participant per year. The long-term commitment and dedication of the nearly 15,000 physician participants will permit successful extension of the multivitamin arm.Project Narrative The approximately 50 percent of U.S. adults who take vitamins spend $23 billion on them each year in the hopes of preventing chronic diseases, yet definitive data regarding the benefits as well as any risks of daily vitamin supplementation are lacking. The Physicians Health Study II is addressing this issue in a large trial among nearly 15,000 U.S. physicians. The results of this trial of a typical multivitamin will have important ramifications for public health, as multivitamins have become increasingly popular.